PRODUCT MONOGRAPH JANUVIA. sitagliptin tablets (as sitagliptin phosphate monohydrate) 25, 50 and 100 mg

Transcription

1 PRODUCT MONOGRAPH JANUVIA sitagliptin tablets (as sitagliptin phosphate monohydrate) 25, 50 and 100 mg Oral Antihyperglycemic Agent DPP-4 inhibitor Incretin Enhancer Merck Canada Inc route Transcanadienne Kirkland, QC Canada H9H 4M7 Date of Revision: March 13, 2017 Submission Control No: JANUVIA (sitagliptin tablets) Page 1 of 51

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION... 3 SUMMARY PRODUCT INFORMATION... 3 INDICATIONS AND CLINICAL USE... 3 CONTRAINDICATIONS... 4 WARNINGS AND PRECAUTIONS... 4 ADVERSE REACTIONS... 7 DRUG INTERACTIONS DOSAGE AND ADMINISTRATION OVERDOSAGE ACTION AND CLINICAL PHARMACOLOGY STORAGE AND STABILITY DOSAGE FORMS, COMPOSITION AND PACKAGING PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION CLINICAL TRIALS DETAILED PHARMACOLOGY TOXICOLOGY REFERENCES PART III: CONSUMER INFORMATION JANUVIA (sitagliptin tablets) Page 2 of 51

3 JANUVIA sitagliptin tablets (as sitagliptin phosphate monohydrate) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Dosage Form / Strength Tablet 25, 50 and 100 mg Clinically Relevant Non-medicinal Ingredients For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. INDICATIONS AND CLINICAL USE Monotherapy JANUVIA (sitagliptin) is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus and for whom metformin is inappropriate due to contraindications or intolerance. Combination with Metformin JANUVIA is indicated in combination with metformin in adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise, plus metformin do not provide adequate glycemic control. Combination with Metformin and a Sulfonylurea JANUVIA is indicated in combination with metformin and a sulfonylurea in adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise, and dual therapy with these agents, do not provide adequate glycemic control. Combination with Insulin JANUVIA is indicated as add-on combination therapy with premixed or long/intermediate acting insulin (with or without metformin) in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control when diet and exercise, and therapy with premixed or long/intermediate acting insulin (with or without metformin) do not provide adequate glycemic control (see CLINICAL TRIALS). Combination with Pioglitazone JANUVIA is indicated in combination with pioglitazone in adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise, plus pioglitazone do not provide adequate glycemic control. JANUVIA (sitagliptin tablets) Page 3 of 51

4 Combination with Metformin and Pioglitazone JANUVIA is indicated in combination with metformin and pioglitazone in adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise, and dual therapy with these agents, do not provide adequate glycemic control. Geriatrics ( 65 years of age): No dosage adjustment is required based on age however, greater sensitivity of some older individuals cannot be ruled out (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY). Pediatrics (<18 years of age): Safety and effectiveness of JANUVIA in pediatric patients have not been established. Therefore, JANUVIA should not be used in this population. CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions and ADVERSE REACTIONS, Post-Marketing Adverse Drug Reactions). For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. WARNINGS AND PRECAUTIONS General JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Pancreatitis There have been reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. In a long-term cardiovascular outcomes trial (see ADVERSE REACTIONS and CLINICAL TRIALS, TECOS Cardiovascular Safety Study), there were two adjudication-confirmed deaths due to acute pancreatitis in patients treated with JANUVIA compared to none in the placebo group. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated. Risk factors for pancreatitis include a history of: pancreatitis, gallstones, alcoholism, or hypertriglyceridemia. Hypoglycemia When JANUVIA was used in combination with metformin and a sulfonylurea, or with a stable dose of insulin (with or without metformin), the incidence of hypoglycemia was increased over that of placebo in combination with metformin and a sulfonylurea or that of placebo in combination with a stable dose of insulin (with or without metformin) (see ADVERSE REACTIONS). To reduce the risk of hypoglycemia associated with these indications, a lower dose of sulfonylurea or insulin may be considered (see DOSAGE AND ADMINISTRATION). JANUVIA (sitagliptin tablets) Page 4 of 51

5 Hypersensitivity Reactions There have been post-marketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes (see CONTRAINDICATIONS and ADVERSE REACTIONS, Post-Marketing Adverse Drug Reactions). Immune Immunocompromised patients: A dose-related mean decrease in absolute lymphocyte count was observed with other members of this class. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of sitagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g. human immunodeficiency virus) is unknown. Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome have not been studied in the sitagliptin clinical program. Therefore, the efficacy and safety profile of sitagliptin in these patients has not been established. Skin With other members of this class, ulcerative and necrotic skin lesions have been reported in monkeys in non-clinical toxicology studies. There is limited experience in patients with diabetic skin complications. In keeping with routine care of the diabetic patient, monitoring for skin disorders is recommended. Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with the use of DPP-4 inhibitors, including JANUVIA. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment. Renal Renal adverse events, including acute renal failure, have been observed during clinical trials and post-marketing use of sitagliptin in patients with and without known risk factors (see ADVERSE REACTIONS). Since JANUVIA is renally excreted, dose adjustment is required in patients with moderate to severe renal impairment as well as end-stage renal disease patients on dialysis (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; and ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). JANUVIA (sitagliptin tablets) Page 5 of 51

6 Hepatic There are limited clinical experiences in patients with moderate hepatic insufficiency and no clinical experience in patients with severe hepatic insufficiency. Use in patients with severe hepatic insufficiency is not recommended (see ACTION AND CLINICAL PHARMACOLOGY). Endocrine and Metabolism The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with JANUVIA, therapeutic alternatives should be considered. Special Populations Pregnant Women: There are no adequate and well-controlled studies in pregnant women; therefore, the safety of JANUVIA in pregnant women is not known. JANUVIA is not recommended for use in pregnancy (see also TOXICOLOGY). Nursing Women: Sitagliptin is secreted in the milk of lactating rats. It is not known whether sitagliptin is secreted in human milk. Therefore, JANUVIA should not be used by a woman who is nursing. Pediatrics (<18 years of age): Safety and effectiveness of JANUVIA in pediatric patients have not been established. Therefore, JANUVIA should not be used in this population. Geriatrics ( 65 years of age): In clinical studies, no overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the geriatric and younger patients, greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney. Renal function should be assessed prior to initiating dosing and periodically thereafter in geriatric patients because they are more likely to have decreased renal function (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY). Monitoring and Laboratory Tests Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA 1c levels, with a goal of decreasing these levels towards the normal range. HbA 1c is especially useful for evaluating long-term glycemic control. 1 Sitagliptin is substantially excreted by the kidney. Renal function should be assessed prior to initiating dosing and periodically thereafter. JANUVIA (sitagliptin tablets) Page 6 of 51

7 ADVERSE REACTIONS Adverse Drug Reaction Overview JANUVIA was generally well tolerated in controlled clinical studies as monotherapy and as part of combination therapy with metformin or combination therapy with metformin and a sulfonylurea agent, or add-on combination therapy with insulin (with or without metformin) or as add-on combination therapy with pioglitazone (with or without metformin). The incidences of serious adverse reactions and discontinuation of therapy due to clinical adverse reactions were generally similar to placebo. The most frequent adverse events in trials of JANUVIA as monotherapy (placebo-controlled) and as add-on combination therapy with metformin (reported regardless of causality, and more common with JANUVIA than other treatments) was nasopharyngitis. The most frequent adverse events with JANUVIA as add-on combination therapy with metformin and a sulfonylurea agent, or as add-on combination therapy with insulin (with or without metformin), was hypoglycemia. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Monotherapy: Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100 mg once daily and patients given placebo. Adverse events, reported regardless of causality assessment, in 1% of patients in these two studies pooled are shown in Table 1. Table 1 Adverse events 1% in any treatment group (regardless of causality) reported in patients treated with JANUVIA 100 mg or placebo in pooled 18 and 24-week placebo-controlled, double-blind clinical trials of JANUVIA as monotherapy Body system/organ class Adverse event Sitagliptin 100 mg n=443 Number of patients (%) Placebo n=363 Eye disorders Conjunctivitis 3 (0.7) 4 (1.1) Gastrointestinal disorders Abdominal pain 5 (1.1) 6 (1.7) Constipation 13 (2.9) 5 (1.4) Diarrhea 19 (4.3) 10 (2.8) Gastritis 2 (0.5) 4 (1.1) Nausea 7 (1.6) 3 (0.8) Vomiting 3 (0.7) 4 (1.1) JANUVIA (sitagliptin tablets) Page 7 of 51

8 Table 1 Adverse events 1% in any treatment group (regardless of causality) reported in patients treated with JANUVIA 100 mg or placebo in pooled 18 and 24-week placebo-controlled, double-blind clinical trials of JANUVIA as monotherapy Body system/organ class Adverse event Sitagliptin 100 mg n=443 Number of patients (%) Placebo n=363 General disorders and administration site conditions Fatigue 5 (1.1) 9 (2.5) Edema peripheral 7 (1.6) 4 (1.1) Pain 0 (0.0) 4 (1.1) Infections and infestations Bronchitis 5 (1.1) 6 (1.7) Gastroenteritis 6 (1.4) 4 (1.1) Influenza 19 (4.3) 16 (4.4) Nasopharyngitis 23 (5.2) 12 (3.3) Pharyngitis 5 (1.1) 1 (0.3) Sinusitis 6 (1.4) 9 (2.5) Upper respiratory tract infection 29 (6.5) 24 (6.6) Urinary tract infection 8 (1.8) 9 (2.5) Viral infection 2 (0.5) 4 (1.1) Viral upper respiratory tract infection 5 (1.1) 1 (0.3) Injury, poisoning and procedural complications Limb injury 3 (0.7) 4 (1.1) Investigations Blood glucose increased 7 (1.6) 13 (3.6) Metabolism and nutrition disorders Hyperglycemia 5 (1.1) 7 (1.9) Hypoglycemia 5 (1.1) 2 (0.6) Musculoskeletal and connective tissue disorders Arthralgia 4 (0.9) 9 (2.5) Back pain 14 (3.2) 12 (3.3) Muscle spasm 6 (1.4) 4 (1.1) Myalgia 6 (1.4) 4 (1.1) Neck pain 1 (0.2) 4 (1.1) Osteoarthritis 5 (1.1) 1 (0.3) Pain in extremity 7 (1.6) 6 (1.7) Nervous system disorders Dizziness 7 (1.6) 8 (2.2) Headache 18 (4.1) 14 (3.9) Paresthesia 4 (0.9) 4 (1.1) Psychiatric disorders Anxiety 3 (0.7) 4 (1.1) Insomnia 4 (0.9) 6 (1.7) JANUVIA (sitagliptin tablets) Page 8 of 51

9 Table 1 Adverse events 1% in any treatment group (regardless of causality) reported in patients treated with JANUVIA 100 mg or placebo in pooled 18 and 24-week placebo-controlled, double-blind clinical trials of JANUVIA as monotherapy Body system/organ class Adverse event Sitagliptin 100 mg n=443 Number of patients (%) Placebo n=363 Respiratory, thoracic and mediastinal disorders Cough 8 (1.8) 10 (2.8) Vascular disorders Hypertension 8 (1.8) 7 (1.9) In a 24-week study which compared sitagliptin and metformin, adverse events, reported regardless of causality assessment, in 1% of patients are shown in Table 2. Table 2 Adverse events 1% in any treatment group (regardless of causality) reported in patients in 24-week active-controlled, double-blind clinical trial of JANUVIA as monotherapy Body system/organ class Adverse event Sitagliptin 100 mg n=528 Number of patients (%) Metformin n=522 Gastrointestinal disorders Abdominal pain 4 (0.8) 6 (1.1) Abdominal pain upper 5 (0.9) 12 (2.3) Constipation 9 (1.7) 5 (1.0) Diarrhea 19 (3.6) 57 (10.9) Dyspepsia 1 (0.2) 7 (1.3) Gastritis 6 (1.1) 11 (2.1) Nausea 6 (1.1) 16 (3.1) Vomiting 2 (0.4) 7 (1.3) General disorders and administration site conditions Fatigue 6 (1.1) 6 (1.1) Infections and infestations Bronchitis 4 (0.8) 7 (1.3) Influenza 12 (2.3) 11 (2.1) Nasopharyngitis 10 (1.9) 17 (3.3) Upper respiratory tract infection 5 (0.9) 11 (2.1) Urinary tract infection 3 (0.6) 13 (2.5) Metabolism and nutrition disorders Hypoglycemia 9 (1.7) 18 (3.4) Musculoskeletal and connective tissue disorders Back pain 9 (1.7) 9 (1.7) Pain in extremity 7 (1.3) 2 (0.4) JANUVIA (sitagliptin tablets) Page 9 of 51

10 Table 2 Adverse events 1% in any treatment group (regardless of causality) reported in patients in 24-week active-controlled, double-blind clinical trial of JANUVIA as monotherapy Body system/organ class Adverse event Sitagliptin 100 mg n=528 Number of patients (%) Metformin n=522 Nervous system disorders Dizziness 9 (1.7) 5 (1.0) Headache 17 (3.2) 17 (3.3) Respiratory, thoracic and mediastinal disorders Cough 1 (0.2) 8 (1.5) Vascular disorders Hypertension 12 (2.3) 4 (0.8) In two monotherapy studies, diarrhea was the only drug-related adverse reaction reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA 100 mg (1.1%) and greater than in patients receiving placebo (0.3%). Combination Therapy Sitagliptin add-on to metformin: In a 24-week placebo-controlled clinical study of patients receiving sitagliptin (100 mg daily) as add-on combination therapy with metformin the incidence of adverse events reported regardless of causality assessment, in 1% of patients are shown in Table 3. Table 3 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin Body system/organ class Adverse event Sitagliptin 100 mg + Metformin n=464 Number of patients (%) Placebo + Metformin n=237 Ear and labyrinth disorders Vertigo 5 (1.1) 4 (1.7) Eye disorders Vision blurred 1 (0.2) 3 (1.3) Gastrointestinal disorders Abdominal pain 2 (0.4) 6 (2.5) Abdominal pain upper 6 (1.3) 2 (0.8) Constipation 5 (1.1) 1 (0.4) Diarrhea 11 (2.4) 6 (2.5) Nausea 6 (1.3) 2 (0.8) Vomiting 5 (1.1) 2 (0.8) General disorders and administration site conditions Fatigue 2 (0.4) 4 (1.7) Edema peripheral 4 (0.9) 3 (1.3) Infections and infestations Bronchitis 12 (2.6) 6 (2.5) Bronchitis acute 2 (0.4) 3 (1.3) Gastroenteritis 4 (0.9) 5 (2.1) Influenza 19 (4.1) 12 (5.1) JANUVIA (sitagliptin tablets) Page 10 of 51

11 Table 3 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin Body system/organ class Adverse event Sitagliptin 100 mg + Metformin n=464 Number of patients (%) Placebo + Metformin n=237 Nasopharyngitis 19 (4.1) 7 (3.0) Pharyngitis 6 (1.3) 1 (0.4) Infections and infestations Pneumonia 5 (1.1) 0 (0.0) Sinusitis 7 (1.5) 2 (0.8) Tooth infection 5 (1.1) 2 (0.8) Upper respiratory tract infection 34 (7.3) 22 (9.3) Urinary tract infection 9 (1.9) 2 (0.8) Injury, poisoning and procedural complications Contusion 5 (1.1) 1 (0.4) Investigations Blood glucose increased 3 (0.6) 6 (2.5) Metabolism and nutrition disorders Hyperglycemia 2 (0.4) 7 (3.0) Hypoglycemia 6 (1.3) 5 (2.1) Musculoskeletal and connective tissue disorders Arthralgia 14 (3.0) 1 (0.4) Back pain 15 (3.2) 6 (2.5) Muscle spasm 1 (0.2) 3 (1.3) Myalgia 1 (0.2) 3 (1.3) Pain in extremity 5 (1.1) 4 (1.7) Shoulder pain 3 (0.6) 3 (1.3) Nervous system disorders Dizziness 7 (1.5) 2 (0.8) Headache 12 (2.6) 7 (3.0) Sciatica 1 (0.2) 3 (1.3) Sinus headache 0 (0.0) 3 (1.3) Psychiatric disorders Insomnia 5 (1.1) 3 (1.3) Renal and urinary disorders Nephrolithiasis 3 (0.6) 3 (1.3) Respiratory, thoracic and mediastinal disorders Cough 14 (3.0) 4 (1.7) Vascular disorders Hypertension 7 (1.5) 6 (2.5) In a combination therapy study with metformin, nausea was the only drug-related adverse reaction reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA (1.1%) and greater than in patients receiving placebo (0.4%). JANUVIA (sitagliptin tablets) Page 11 of 51

12 In pooled studies of up to one year duration which compared sitagliptin added to metformin or a sulfonylurea agent (glipizide) added to metformin, adverse events, reported regardless of causality assessment, in 1% of patients are shown in Table 4. Table 4 Adverse events 1% in any treatment group (regardless of causality) reported in patients from double-blind clinical trials of JANUVIA in add-on combination use with metformin in studies up to one year compared to a sulfonylurea agent (glipizide) Number of patients (%) Body system/organ class Adverse event Sitagliptin 100 mg + Metformin n=979 Glipizide + Metformin n=748 Gastrointestinal disorders Abdominal pain 10 (1.0) 6 (0.8) Abdominal pain upper 13 (1.3) 7 (0.9) Constipation 17 (1.7) 13 (1.7) Diarrhea 42 (4.3) 36 (4.8) Dyspepsia 14 (1.4) 12 (1.6) Nausea 19 (1.9) 16 (2.1) Toothache 2 (0.2) 13 (1.7) Vomiting 11 (1.1) 9 (1.2) General disorders and administration site conditions Fatigue 20 (2.0) 8 (1.1) Non-cardiac chest pain 10 (1.0) 6 (0.8) Edema peripheral 16 (1.6) 14 (1.9) Infections and infestations Bronchitis 27 (2.8) 22 (2.9) Cellulitis 7 (0.7) 10 (1.3) Gastroenteritis 19 (1.9) 13 (1.7) Gastroenteritis viral 8 (0.8) 9 (1.2) Herpes zoster 4 (0.4) 8 (1.1) Influenza 35 (3.6) 32 (4.3) Nasopharyngitis 75 (7.7) 49 (6.6) Sinusitis 20 (2.0) 12 (1.6) Upper respiratory tract infection 78 (8.0) 70 (9.4) Urinary tract infection 41 (4.2) 21 (2.8) Investigations Blood glucose decreased 5 (0.5) 16 (2.1) Blood glucose increased 13 (1.3) 5 (0.7) Weight increased 1 (0.1) 8 (1.1) Metabolism and nutrition disorders Hyperglycemia 10 (1.0) 6 (0.8) Hypoglycemia 32 (3.3) 217 (29.0) Musculoskeletal and connective tissue disorders Arthralgia 34 (3.5) 29 (3.9) Back pain 39 (4.0) 32 (4.3) Muscle spasms 9 (0.9) 8 (1.1) Neck pain 4 (0.4) 8 (1.1) Osteoarthritis 18 (1.8) 5 (0.7) Pain in extremity 23 (2.3) 9 (1.2) Shoulder pain 7 (0.7) 14 (1.9) JANUVIA (sitagliptin tablets) Page 12 of 51

13 Table 4 Adverse events 1% in any treatment group (regardless of causality) reported in patients from double-blind clinical trials of JANUVIA in add-on combination use with metformin in studies up to one year compared to a sulfonylurea agent (glipizide) Number of patients (%) Body system/organ class Adverse event Sitagliptin 100 mg + Metformin n=979 Glipizide + Metformin n=748 Nervous system disorders Dizziness 26 (2.7) 14 (1.9) Headache 34 (3.5) 31 (4.1) Hypoaesthesia 3 (0.3) 11 (1.5) Psychiatric disorders Anxiety 13 (1.3) 7 (0.9) Depression 10 (1.0) 7 (0.9) Insomnia 12 (1.2) 11 (1.5) Reproductive system and breast disorders Erectile dysfunction 6 (0.6) 8 (1.1) Respiratory, thoracic and mediastinal disorders Cough 19 (1.9) 23 (3.1) Pharyngolaryngeal pain 10 (1.0) 9 (1.2) Sinus congestion 5 (0.5) 8 (1.1) Eczema 4 (0.4) 12 (1.6) Vascular disorders Hypertension 33 (3.4) 29 (3.9) Combination Therapy: Sitagliptin add-on to Metformin and a Sulfonylurea In a 24-week placebo-controlled study of JANUVIA 100 mg in combination with metformin and glimepiride (JANUVIA, N=116; placebo, N=113), the incidence of adverse events, reported regardless of causality assessment, in 1% of patients are shown in Table 5. The overall incidence of adverse events with JANUVIA was higher than with placebo, in part related to higher incidence of hypoglycemia (see Table 5). Table 5 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and a sulfonylurea agent (glimepiride) Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Glimepiride n=116 Number of patients (%) Placebo + Metformin + Glimepiride n=113 Ear and Labyrinth Disorders Vertigo 2 (1.7) 0 (0.0) Eye Disorders Diabetic retinopathy 0 (0.0) 2 (1.8) Vision blurred 0 (0.0) 2 (1.8) Gastrointestinal disorders Abdominal pain upper 2 (1.7) 2 (1.8) Constipation 4 (3.4) 0 (0.0) Diarrhea 1 (0.9) 4 (3.5) Dyspepsia 3 (2.6) 2 (1.8) Gastritis 0 (0.0) 4 (3.5) JANUVIA (sitagliptin tablets) Page 13 of 51

14 Table 5 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and a sulfonylurea agent (glimepiride) Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Glimepiride n=116 Number of patients (%) Placebo + Metformin + Glimepiride n=113 Toothache 2 (1.7) 2 (1.8) Vomiting 2 (1.7) 1 (0.9) General disorders and administration site conditions Fatigue 0 (0.0) 3 (2.7) Non-Cardiac chest pain 2 (1.7) 1 (0.9) Pyrexia 0 (0.0) 2 (1.8) Hepatobiliary disorders Cholelithiasis 0 (0.0) 2 (1.8) Infections and infestations Bronchitis 2 (1.7) 2 (1.8) Gastroenteritis 3 (2.6) 0 (0.0) Gastroenteritis viral 2 (1.7) 2 (1.8) Influenza 3 (2.6) 2 (1.8) Nasopharyngitis 7 (6.0) 9 (8.0) Pharyngitis 1 (0.9) 3 (2.7) Pneumonia 3 (2.6) 0 (0.0) Rhinitis 2 (1.7) 0 (0.0) Sinusitis 1 (0.9) 2 (1.8) Tooth abscess 2 (1.7) 1 (0.9) Upper respiratory tract infection 8 (6.9) 9 (8.0) Urinary tract infection 2 (1.7) 1 (0.9) Injury, poisoning and procedural complications Fall 0 (0.0) 3 (2.7) Polytraumatism 1 (0.9) 2 (1.8) Investigations Blood glucose decreased 0 (0.0) 2 (1.8) Metabolism and nutrition disorders Hypoglycemia 19 (16.4) 1 (0.9) Musculoskeletal and connective tissue disorders Arthralgia 5 (4.3) 1 (0.9) Back pain 1 (0.9) 2 (1.8) Muscle spasms 2 (1.7) 1 (0.9) Osteoarthritis 2 (1.7) 0 (0.0) Pain in extremity 4 (3.4) 1 (0.9) Shoulder pain 0 (0.0) 2 (1.8) Nervous system disorders Dizziness 3 (2.6) 1 (0.9) Headache 8 (6.9) 3 (2.7) Hypoaesthesia 2 (1.7) 0 (0.0) Somnolence 0 (0.0) 2 (1.8) JANUVIA (sitagliptin tablets) Page 14 of 51

15 Table 5 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and a sulfonylurea agent (glimepiride) Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Glimepiride n=116 Number of patients (%) Placebo + Metformin + Glimepiride n=113 Respiratory, thoracic and mediastinal disorders Asthma 2 (1.7) 1 (0.9) Skin and subcutaneous tissue disorders Pruritus 2 (1.7) 1 (0.9) Rash 2 (1.7) 1 (0.9) Vascular disorders Hypertension 2 (1.7) 0 (0.0) In a combination therapy study with metformin and a sulfonylurea, hypoglycemia (JANUVIA 13.8%; placebo 0.9%) and constipation (JANUVIA 1.7%; placebo 0.0%) were the only drug-related adverse reactions reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA and metformin and a sulfonylurea and greater than in patients receiving placebo and metformin and a sulfonylurea. Combination Therapy: Add-on with Insulin (with or without metformin) In a 24-week placebo-controlled study of JANUVIA 100 mg in combination with stable-dose insulin (with or without metformin) (JANUVIA, N=322; placebo, N=319), the incidence of adverse reactions, reported regardless of causality assessment, in 1% of patients are shown in Table 6. The overall incidence of adverse events with JANUVIA was higher than with placebo, in part related to higher incidence of hypoglycemia (see Table 6) Table 6 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with stable dose insulin (with or without metformin) Body system/organ class Adverse event Sitagliptin 100 mg + Insulin (+/- Metformin) n=322 Number of patients (%) Placebo + Insulin (+/- Metformin) n=319 Gastrointestinal Disorders Constipation 6 (1.9) 1 (0.3) Diarrhea 6 (1.9) 5 (1.6) Nausea 4 (1.2) 5 (1.6) Vomiting 5 (1.6) 2 (0.6) Infections and infestations Bronchitis 6 (1.9) 5 (1.6) Gastroenteritis 3 (0.9) 5 (1.6) Influenza 13 (4.0) 12 (3.8) Nasopharyngitis 10 (3.1) 8 (2.5) Sinusitis 4 (1.2) 4 (1.3) Upper respiratory tract infection 10 (3.1) 11 (3.4) Urinary tract infection 9 (2.8) 6 (1.9) JANUVIA (sitagliptin tablets) Page 15 of 51

16 Table 6 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with stable dose insulin (with or without metformin) Body system/organ class Adverse event Sitagliptin 100 mg + Insulin (+/- Metformin) n=322 Number of patients (%) Placebo + Insulin (+/- Metformin) n=319 Investigations Alanine aminotransferase increased 4 (1.2) 1 (0.3) Creatinine renal clearance decreased 5 (1.6) 0 (0.0) Metabolism and nutrition disorders Hyperglycemia 5 (1.6) 2 (0.6) Hypoglycemia 50 (15.5) 25 (7.8) Musculoskeletal and connective tissue disorders Arthralgia 4 (1.2) 6 (1.9) Back pain 6 (1.9) 2 (0.6) Muscle spasms 3 (0.9) 5 (1.6) Pain in extremity 6 (1.9) 3 (0.9) Nervous system disorders Dizziness 5 (1.6) 3 (0.9) Headache 9 (2.8) 3 (0.9) Respiratory, thoracic and mediastinal disorders Cough 5 (1.6) 3 (0.9) In a combination therapy study with stable dose insulin (with or without metformin), hypoglycemia (JANUVIA, 9.6%; placebo, 5.3%), influenza (JANUVIA, 1.2%, placebo, 0.3%), and headache (JANUVIA, 1.2%, placebo, 0.0%) were the only drug-related adverse reactions reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA and greater than in patients receiving placebo. Combination Therapy: Sitagliptin add-on to Pioglitazone (with or without Metformin) In a 24-week placebo-controlled clinical study of patients receiving sitagliptin (100 mg daily) as add-on combination therapy with pioglitazone, the incidence of adverse events reported regardless of causality assessment, in 1% of patients are shown in Table 7. Table 7 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination with pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Pioglitazone n=175 Number of patients (%) Placebo + Pioglitazone n=178 Ear and Labyrinth Disorders Vertigo 0 (0.0) 3 (1.7) Eye Disorders Cataract 0 (0.0) 3 (1.7) Vision Blurred 2 (1.1) 1 (0.6) JANUVIA (sitagliptin tablets) Page 16 of 51

17 Table 7 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination with pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Pioglitazone n=175 Number of patients (%) Placebo + Pioglitazone n=178 Gastrointestinal disorders Abdominal pain 2 (1.1) 0 (0.0) Abdominal pain lower 2 (1.1) 0 (0.0) Abdominal pain upper 2 (1.1) 0 (0.0) Constipation 2 (1.1) 2 (1.1) Diarrhea 3 (1.7) 2 (1.1) Dyspepsia 2 (1.1) 1 (0.6) Flatulence 2 (1.1) 0 (0.0) Nausea 2 (1.1) 0 (0.0) General disorders and administration site conditions Chest pain 2 (1.1) 0 (0.0) Fatigue 1 (0.6) 3 (1.7) Feeling abnormal 2 (1.1) 0 (0.0) Oedema 2 (1.1) 1 (0.6) Oedema peripheral 7 (4.0) 5 (2.8) Hepatobiliary Disorders Cholelithiasis 0 (0.0) 2 (1.1) Infections and infestations Bronchitis 3 (1.7) 1 (0.6) Cellulitis 2 (1.1) 1 (0.6) Influenza 6 (3.4) 5 (2.8) Nasopharyngitis 7 (4.0) 7 (3.9) Pharyngitis 2 (1.1) 2 (1.1) Pneumonia 0 (0.0) 3 (1.7) Pyoderma 2 (1.1) 0 (0.0) Sinusitis 2 (1.1) 2 (1.1) Tinea Pedis 2 (1.1) 0 (0.0) Upper respiratory tract infection 11 (6.3) 6 (3.4) Urinary tract infection 1 (0.6) 2 (1.1) Viral infection 2 (1.1) 1 (0.6) Injury, poisoning and procedural complications Joint sprain 2 (1.1) 2 (1.1) Investigations Blood glucose increased 1 (0.6) 2 (1.1) Weight increased 5 (2.9) 5 (2.8) Metabolism and nutrition disorders Hypoglycemia 2 (1.1) 0 (0.0) Musculoskeletal and connective tissue disorders Arthralgia 5 (2.9) 4 (2.2) Back pain 3 (1.7) 5 (2.8) Musculoskeletal stiffness 2 (1.1) 0 (0.0) Myalgia 0 (0.0) 2 (1.1) Neck pain 0 (0.0) 2 (1.1) JANUVIA (sitagliptin tablets) Page 17 of 51

18 Table 7 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 24-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination with pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Pioglitazone n=175 Number of patients (%) Placebo + Pioglitazone n=178 Osteoarthritis 3 (1.7) 3 (1.7) Pain in extremity 4 (2.3) 3 (1.7) Tendonitis 0 (0.0) 2 (1.1) Nervous system disorders Dizziness 3 (1.7) 2 (1.1) Headache 9 (5.1) 7 (3.9) Psychiatric disorders Anxiety 1 (0.6) 2 (1.1) Depression 4 (2.3) 2 (1.1) Libido decreased 2 (1.1) 0 (0.0) Respiratory, thoracic and mediastinal disorders Cough 3 (1.7) 3 (1.7) Skin and subcutaneous tissue disorders Dermatitis allergic 0 (0.0) 2 (1.1) In a combination therapy study with pioglitazone, hypoglycemia (JANUVIA, 1.1%, placebo, 0.0%), flatulence (JANUVIA, 1.1%, placebo, 0.0%), weight increase (JANUVIA, 2.3%, placebo, 1.7%), and headache (JANUVIA, 1.7%, placebo, 1.1%) were the only drug-related adverse reactions reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA and greater than in patients receiving placebo. In a 26-week placebo-controlled clinical study of patients receiving sitagliptin (100 mg daily) as add-on combination therapy with metformin and pioglitazone, the incidence of adverse events reported regardless of causality assessment, in 1% of patients are shown in Table 8. Table 8 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 26-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Pioglitazone n=157 Number of patients (%) Placebo + Metformin + Pioglitazone n=156 Ear and Labyrinth Disorders Cerumen impaction 2 (1.3) 1 (0.6) Eye Disorders Conjunctivitis 3 (1.9) 1 (0.6) Ocular hyperaemia 0 (0.0) 2 (1.3) Gastrointestinal disorders Abdominal pain upper 1 (0.6) 2 (1.3) Constipation 2 (1.3) 1 (0.6) Dental Caries 2 (1.3) 1 (0.6) Diarrhea 3 (1.9) 4 (2.6) JANUVIA (sitagliptin tablets) Page 18 of 51

19 Table 8 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 26-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Pioglitazone n=157 Number of patients (%) Placebo + Metformin + Pioglitazone n=156 Dyspepsia 1 (0.6) 2 (1.3) Gastritis 0 (0.0) 2 (1.3) Toothache 2 (1.3) 0 (0.0) Vomiting 2 (1.3) 0 (0.0) General disorders and administration site conditions Fatigue 0 (0.0) 2 (1.3) Oedema peripheral 3 (1.9) 7 (4.5) Infections and infestations Bronchitis 3 (1.9) 1 (0.6) Cellulitis 2 (1.3) 0 (0.0) Gastroenteritis 2 (1.3) 0 (0.0) Gastroenteritis viral 2 (1.3) 0 (0.0) Herpes zoster 2 (1.3) 0 (0.0) Influenza 2 (1.3) 3 (1.9) Nasopharyngitis 5 (3.2) 5 (3.2) Tooth abscess 0 (0.0) 2 (1.3) Upper respiratory tract infection 13 (8.3) 14 (9.0) Urinary tract infection 5 (3.2) 6 (3.8) Injury, poisoning and procedural complications Muscle strain 2 (1.3) 0 (0.0) Investigations Blood creatine phosphokinase increased 1 (0.6) 3 (1.9) Glomerular filtration rate decreased 2 (1.3) 0 (0.0) Lymphocyte count increased 2 (1.3) 1 (0.6) Neutrophil count decreased 2 (1.3) 1 (0.6) Metabolism and nutrition disorders Hyperglycemia 2 (1.3) 2 (1.3) Hypoglycemia 10 (6.4) 7 (4.5) Musculoskeletal and connective tissue disorders Arthralgia 2 (1.3) 3 (1.9) Back pain 7 (4.5) 4 (2.6) Muscle spasms 2 (1.3) 0 (0.0) Musculoskeletal pain 3 (1.9) 4 (2.6) Pain in extremity 5 (3.2) 2 (1.3) Nervous system disorders Headache 1 (0.6) 2 (1.3) Psychiatric disorders Depression 4 (2.5) 1 (0.6) Stress 2 (1.3) 0 (0.0) Respiratory, thoracic and mediastinal disorders JANUVIA (sitagliptin tablets) Page 19 of 51

20 Table 8 Adverse events 1% in any treatment group (regardless of causality) reported in patients in a 26-week placebo-controlled, double-blind clinical trial of JANUVIA in add-on combination use with metformin and pioglitazone Body system/organ class Adverse event Sitagliptin 100 mg + Metformin + Pioglitazone n=157 Number of patients (%) Placebo + Metformin + Pioglitazone n=156 Cough 2 (1.3) 2 (1.3) Oropharyngeal pain 2 (1.3) 0 (0.0) Rhinitis allergic 2 (1.3) 0 (0.0) In a combination therapy study with pioglitazone and metformin, hypoglycemia (JANUVIA, 3.2%; placebo, 1.9%) was the only drug-related adverse reaction reported by the investigator that occurred with an incidence 1% in patients receiving JANUVIA and greater than in patients receiving placebo. Less Common Clinical Trial Adverse Drug Reactions 0.1% and <1% (Drug-Related and Greater than Placebo in Pooled Monotherapy and in Individual Placebo-Controlled Studies) Blood and Lymphatic System Disorders: anemia Cardiac Disorders: bundle branch block, palpitations Eye Disorders: vision blurred Gastrointestinal Disorders: abdominal discomfort, abdominal pain upper, abdominal tenderness, constipation, diarrhea, dry mouth, dyspepsia, flatulence, reflux esophagitis disease, frequent bowel movements, gastroesophageal reflux disease, irritable bowel syndrome, retching, salivary hypersecretion General Disorders and Administration Site Conditions: asthenia, chest discomfort, face edema, fatigue, feeling abnormal, hunger, irritability, malaise, peripheral edema, edema, pain, pyrexia, thirst, xerosis Hepatobiliary Disorders: hepatic steatosis Infections and Infestations: gastric ulcer helicobacter, genital abscess, helicobacter gastritis, localized infection, oropharyngeal candidiasis, sinusitis, upper respiratory tract infection, urinary tract infection Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood glucose decreased, blood glucose increased, blood pressure decreased, blood pressure increased, creatinine renal clearance decreased, glomerular filtration rate decreased, white blood cell count increased Metabolism and Nutrition Disorders: decreased appetite, hypoglycemia Musculoskeletal and Connective Tissue Disorders: muscle fatigue, muscle tightness Nervous System Disorders: coordination abnormal, dizziness, headache, migraine, neuropathy peripheral, parosmia, somnolence Psychiatric Disorders: anxiety, depression, insomnia, libido decreased Renal and Urinary Disorders: renal disorders Reproductive System and Breast Disorders: balanoposthitis, dysmenorrhea, erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: cough JANUVIA (sitagliptin tablets) Page 20 of 51

21 Skin and Subcutaneous Tissue Disorders: angioneurotic oedema, dermatitis acneiform, dry skin, erythema, exanthem, hyperhidrosis, leukocytoclastic vasculitis, nail disorder, prurigo, pruritus generalized, rash, rash macular, rosacea, urticaria Vascular Disorders: orthostatic hypotension Atrial fibrillation/atrial flutter: In a pooled analysis of randomized clinical trials, the pooled terms atrial fibrillation/atrial flutter were observed at an incidence rate of 0.45 events per 100 patient-years in the sitagliptin-exposed group compared to 0.28 events per 100 patient-years in the non-exposed group. TECOS Cardiovascular Safety Study: For details pertaining to study design and patient population, see CLINICAL TRIALS, TECOS Cardiovascular Safety Study. The incidence of adjudication-confirmed pancreatitis events was higher in the JANUVIA group (0.3%) compared to the placebo group (0.2%). The JANUVIA group experienced a greater number of severe cases of pancreatitis including two confirmed deaths due to pancreatitis, compared to none in the placebo group. Among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 2.7% in patients treated with JANUVIA and 2.5% in patients treated with placebo; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 1.0% in patients treated with JANUVIA and 0.7% in placebo-treated patients. Abnormal Hematologic and Clinical Chemistry Findings The incidence of laboratory adverse experiences was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. In most clinical studies, a slight decrease in alkaline phosphatase and small increases in uric acid and white blood cell count (due to an increase in neutrophils) were observed. In active comparator studies versus metformin or versus a sulfonylurea agent (glipizide) similar changes were seen in alkaline phosphatase and uric acid. JANUVIA (sitagliptin tablets) Page 21 of 51

22 Study Mean Change from Baseline (Standard Error) Alkaline Uric Acid Treatment Group Phosphatase (mg/dl) (IU/L) WBC (cell/microl) Placebo-controlled Sitagliptin -5.3 (0.5) 0.26 (0.04) (71.7) (monotherapy) 1 Placebo -0.8 (0.5) (0.05) 58.6 (80.0) Active-controlled Sitagliptin -3.9 (0.5) -0.0 (0.0) (77.7) (monotherapy) 2 Metformin -4.7 (0.5) 0.1 (0.0) (66.6) Placebo-controlled (addon Sitagliptin -3.1 (0.4) 0.17 (0.04) (64.3) to metformin) 3 Placebo -1.3 (0.7) 0.05 (0.06) (98.8) Active-controlled Sitagliptin -5.7 (0.5) 0.21 (0.05) (67.4) (add-on to metformin) 4 Glipizide -3.4 (0.5) 0.20 (0.05) 86.0 (62.5) 1 pooled data from studies 3 and 4; see CLINICAL TRIALS, Table 10 2 study 5; see CLINICAL TRIALS, Table 10 3 study 1; see CLINICAL TRIALS, Table 10 4 study 2; see CLINICAL TRIALS, Table 10 In a combination therapy study with stable dose insulin (with or without metformin), a greater proportion of patients was observed to have a decrease in hemoglobin 1.5 g/dl in the sitagliptin group (6.0%) compared with the placebo group (2.1%). No adverse experiences of anemia or hemoglobin decreased were reported in the sitagliptin group. Post-Marketing Adverse Drug Reactions The following adverse reactions have been identified during post-marketing use of JANUVIA as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions, including Stevens-Johnson syndrome (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions) Renal and urinary disorders: worsening renal function, including acute renal failure (sometimes requiring dialysis) (see WARNINGS AND PRECAUTIONS) Gastrointestinal disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see WARNINGS AND PRECAUTIONS); vomiting Musculoskeletal and connective tissue disorders: arthralgia; myalgia; pain in extremity; back pain Skin and subcutaneous tissue disorders: pruritus, bullous pemphigoid (see WARNINGS AND PRECAUTIONS, Skin) DRUG INTERACTIONS Overview Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit JANUVIA (sitagliptin tablets) Page 22 of 51

23 p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways. Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low. Drug-Drug Interactions In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT). Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin or JANUVIA in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport. Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, were not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9. The effect of sulfonylureas on the pharmacokinetics of sitagliptin was not assessed. Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism. Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP2C8-mediated metabolism. Clinically meaningful interactions with pioglitazone are not expected because pioglitazone predominantly undergoes CYP2C8- or CYP3A4-mediated metabolism. The effect of thiazolidinediones on the pharmacokinetics of sitagliptin was not assessed. Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Since S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor. Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steadystate pharmacokinetics of norethindrone or ethinyl estradiol. JANUVIA (sitagliptin tablets) Page 23 of 51

24 Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma C max by 18%. These increases are not considered likely to be clinically meaningful. No dosage adjustment of digoxin or JANUVIA is recommended. Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100-mg oral dose of JANUVIA and a single 600-mg oral dose of cyclosporine increased the AUC and C max of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors. No dosage adjustment for JANUVIA is recommended when coadministered with cyclosporine or other p-glycoprotein inhibitors (e.g., ketoconazole). Drug-Food Interactions There are no known interactions with food. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Drug-Lifestyle Interactions No studies of the effects of JANUVIA on the ability to drive and use machines have been performed. However, JANUVIA is not expected to affect the ability to drive and use machines. When JANUVIA is used in combination with metformin a sulfonylurea or in combination with insulin (with or without metformin) patients should be advised to take precautions to avoid hypoglycemia while driving or using machinery. DOSAGE AND ADMINISTRATION Dosing Considerations JANUVIA can be taken with or without food. Recommended Dose and Dosage Adjustment The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin, with metformin and a sulfonylurea, with insulin (with or without metformin), or with pioglitazone (with or without metformin). When JANUVIA is used in combination with metformin and a sulfonylurea or with insulin (with or without metformin); a lower dose of sulfonylurea or insulin may be considered to reduce the risk of hypoglycemia (see WARNINGS AND PRECAUTIONS, Hypoglycemia). JANUVIA (sitagliptin tablets) Page 24 of 51

25 Patients with Renal Insufficiency: JANUVIA is renally excreted. To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, dosage recommendations are as follows: For patients with mild renal insufficiency (creatinine clearance [CrCl] 50 ml/min), no dosage adjustment for JANUVIA is required. For patients with moderate renal insufficiency (CrCl 30 to <50 ml/min), the dose of JANUVIA is 50 mg once daily. For patients with severe renal insufficiency (CrCl <30 ml/min) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of dialysis. Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula (see WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY and CLINICAL TRIALS, Patients with Renal Insufficiency). When considering the use of sitagliptin in combination with another anti-diabetic product, its conditions for use in patients with renal impairment should be followed. Patients with Hepatic Insufficiency: Use of sitagliptin in patients with severe hepatic insufficiency is not recommended. Geriatrics: No dosage adjustment is necessary for geriatric patients. Pediatrics: There are no data available on the use of JANUVIA in patients younger than 18 years of age. Therefore, use of JANUVIA in pediatric patients is not recommended. Missed Dose If a dose of JANUVIA is missed, it should be taken as soon as the patient remembers. A double dose of JANUVIA should not be taken on the same day. OVERDOSAGE For management of a suspected drug overdose, contact your regional Poison Control Centre. During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg JANUVIA (see ACTION AND CLINICAL PHARMACOLOGY). There is no experience with doses above 800 mg in clinical trials. JANUVIA (sitagliptin tablets) Page 25 of 51